IAP antagonist tolinapant (ASTX660) in combination with pembrolizumab in advanced solid tumors: a phase I trial
Abstract
Successful cancer immunotherapy requires not only tumor cell killing but also the activation of innate and adaptive immune responses. The inhibitor of apoptosis (IAP) proteins cIAP1, cIAP2 and XIAP act as key suppressors of RIPK1-driven immunogenic cell death, thereby enabling tumor immune evasion and limiting the effectiveness of immune checkpoint blockade (ICB). ASTX660 (tolinapant) is a non-peptidomimetic antagonist with a balanced activity against all clinically relevant IAPs, designed to lower the TNF cytotoxicity threshold and sensitize tumors to T cell-mediated killing. Here, we present results from the phase I ASTEROID trial (NCT05082259), evaluating ASTX660 in combination with pembrolizumab in patients with advanced solid tumors. Primary endpoints were recommended phase 2 dose (RP2D) and safety, while secondary endpoints were anti-tumor activity and pharmacokinetics. The combination was well tolerated and demonstrated early evidence of efficacy. RP2D was ASTX660 150 mg (7-days-on/14-days-off) with pembrolizumab. Overall response rate was 33%, including responses in ER⁺ breast cancers typically resistant to ICB. Integrated translational analyses reveal that response is associated with a TNF/IFN-enriched inflammatory tumor microenvironment, increased tumor antigenicity and enhanced TCR clonal diversity, whereas resistance correlates with a CCR4/6/7/8-driven TAM/Treg-dominant niche. Together, these results provide clinical proof-of-concept that dual IAP and PD-1 blockade sensitize tumors, while identifying candidate biomarkers to guide patient stratification in future studies.
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BibTeX
@article{tiu2026antagonist,
title = {{IAP antagonist tolinapant (ASTX660) in combination with pembrolizumab in advanced solid tumors: a phase I trial}},
author = {Crescens Tiu and Wing Yau and Tencho Tenev and Daniel Lionarons and Ching Leung and Victoria Sanchez-Perez and Giovanni Codacci-Pisanelli and Xiaoran Lai and Anna Zachariou and Aasia Hussain and Toby Prout and Mona Parmar and Bindu Baikady and Maria Goicoechea and Scott Layzell and Naomi Guppy and Ioannis Roxanis and Thomas Lund and Diego Carlos Dos Reis and Camila Pereira Almeida and Tatiany Luiza Silveira and Ana Ferreira and Bora Gurel and Claudia Bertan and Mateus Crespo and Penny Flohr and Ann-Marie Baker and Trevor Graham and Luis Zapata and Claudio Salas and Soham Mandal and Alan Dunlop and Martin Sims and George Ward and Tomoko Smyth and Simone Jueliger and Matthew Davis and Ilya Potapov and Aram Oganesian and Danna Chan and Mattias Leino and Subham Basu and Andre Samson and James M. Murphy and Nina Tunariu and Edward W. Johnston and Alistair Ring and Nick Turner and Andrew N. J. Tutt and Amanda Swain and Anna Minchom and Adam Sharp and Alec Paschalis and Udai Banerji and Johann de Bono and Bristi Basu and Christina Yap and Syed Haider and Juanita Lopez and Pascal Meier},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77552-7},
url = {https://www.nature.com/articles/s41467-026-77552-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - IAP antagonist tolinapant (ASTX660) in combination with pembrolizumab in advanced solid tumors: a phase I trial
AU - Crescens Tiu
AU - Wing Yau
AU - Tencho Tenev
AU - Daniel Lionarons
AU - Ching Leung
AU - Victoria Sanchez-Perez
AU - Giovanni Codacci-Pisanelli
AU - Xiaoran Lai
AU - Anna Zachariou
AU - Aasia Hussain
AU - Toby Prout
AU - Mona Parmar
AU - Bindu Baikady
AU - Maria Goicoechea
AU - Scott Layzell
AU - Naomi Guppy
AU - Ioannis Roxanis
AU - Thomas Lund
AU - Diego Carlos Dos Reis
AU - Camila Pereira Almeida
AU - Tatiany Luiza Silveira
AU - Ana Ferreira
AU - Bora Gurel
AU - Claudia Bertan
AU - Mateus Crespo
AU - Penny Flohr
AU - Ann-Marie Baker
AU - Trevor Graham
AU - Luis Zapata
AU - Claudio Salas
AU - Soham Mandal
AU - Alan Dunlop
AU - Martin Sims
AU - George Ward
AU - Tomoko Smyth
AU - Simone Jueliger
AU - Matthew Davis
AU - Ilya Potapov
AU - Aram Oganesian
AU - Danna Chan
AU - Mattias Leino
AU - Subham Basu
AU - Andre Samson
AU - James M. Murphy
AU - Nina Tunariu
AU - Edward W. Johnston
AU - Alistair Ring
AU - Nick Turner
AU - Andrew N. J. Tutt
AU - Amanda Swain
AU - Anna Minchom
AU - Adam Sharp
AU - Alec Paschalis
AU - Udai Banerji
AU - Johann de Bono
AU - Bristi Basu
AU - Christina Yap
AU - Syed Haider
AU - Juanita Lopez
AU - Pascal Meier
PY - 2026
DA - 2026/09/30
JO - Nature Communications
DO - 10.1038/s41467-026-77552-7
UR - https://www.nature.com/articles/s41467-026-77552-7
AB - Successful cancer immunotherapy requires not only tumor cell killing but also the activation of innate and adaptive immune responses. The inhibitor of apoptosis (IAP) proteins cIAP1, cIAP2 and XIAP act as key suppressors of RIPK1-driven immunogenic cell death, thereby enabling tumor immune evasion and limiting the effectiveness of immune checkpoint blockade (ICB). ASTX660 (tolinapant) is a non-peptidomimetic antagonist with a balanced activity against all clinically relevant IAPs, designed to lower the TNF cytotoxicity threshold and sensitize tumors to T cell-mediated killing. Here, we present results from the phase I ASTEROID trial (NCT05082259), evaluating ASTX660 in combination with pembrolizumab in patients with advanced solid tumors. Primary endpoints were recommended phase 2 dose (RP2D) and safety, while secondary endpoints were anti-tumor activity and pharmacokinetics. The combination was well tolerated and demonstrated early evidence of efficacy. RP2D was ASTX660 150 mg (7-days-on/14-days-off) with pembrolizumab. Overall response rate was 33%, including responses in ER⁺ breast cancers typically resistant to ICB. Integrated translational analyses reveal that response is associated with a TNF/IFN-enriched inflammatory tumor microenvironment, increased tumor antigenicity and enhanced TCR clonal diversity, whereas resistance correlates with a CCR4/6/7/8-driven TAM/Treg-dominant niche. Together, these results provide clinical proof-of-concept that dual IAP and PD-1 blockade sensitize tumors, while identifying candidate biomarkers to guide patient stratification in future studies.
SN - 2041-1723
ER -